Abstract PIKE (PI 3-kinase Enhancer) is a brain specific GTPase that enhances PI 3-kinase (PI3K) activity. PIKE binds and stimulates PI3K activity in a GTP-dependent manner. PLC-g1 activates PIKE by acting as a guanine nucleotide exchange factor (GEF). In hippocampal neurons, activation of group I metabotropic glutamate receptors (mGluRIs) stimulates formation of an mGluRI-Homer-PIKE-L complex, leading to activation of PI3K and prevention of neuronal apoptosis. Our preliminary studies show that netrin-1 induces interaction of UNC5B, a netrin receptor, with PIKE-L, which triggers activation of PI3K signaling, and prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. The association between PIKE and UNC5B is mediated by netrin-activated Fyn tyrosine kinase. In alignment with this observation, PIKE deficient mice are vulnerable to neuroexcitotoxicity or stroke-provoked neuronal apoptosis. Moreover, we found that Akt feeds back and phosphorylates PIKE-L. However, the biological significance of this event remains elusive. We hypothesize that PIKE is critical for NGF-provoked neuronal survival, netrin-mediated neuronal survival and netrin receptor dimerization. The objective of this proposed research is to determine the physiological functions of GTPase PIKE (PI 3-Kinase Enhancer) in various cellular processes including NGF-mediated neuronal survival and netrin-1 signaling using PIKE knockout mice. Characterization of the molecular mechanisms by PIKE in the cell death machinery in neurons not only leads to a better understanding of nervous system development but also promises to provide multiple points of therapeutic intervention for neurodegenerative diseases.